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A recent study led by Assistant Professor of Gerontology Ryo Sanabria has identified a key protein that helps regulate the actin cytoskeleton, a scaffold of proteins within cells that makes their proper structure and function possible.

A review of genes both in the worm C. elegans and in human cells published in the journal Aging Cell revealed that the protein BET-1 promotes the proper function of actin, the protein that makes up the building blocks of the cytoskeleton. Overexpression of the gene for BET-1 appears to preserve actin function at later ages and improve health and lifespan in worms, according to the study.

Many of the cellular processes that depend on the actin cytoskeleton – from cell division to recycling damaged parts of the cell – deteriorate during aging and exposure to stress as the cytoskeleton breaks down. However, the regulatory mechanisms involved in preservation of cytoskeletal form and function are not well-understood, Sanabria said. With the cytoskeleton being necessary for numerous cellular functions as well as maintaining its very shape, understanding its regulation and how well it responds to stressors over time could shed light on many aging-related illnesses.

How stress and aging affect cells

A large part of Sanabria’s research interest is the intersection between stress and aging, including how organisms respond to stress, how stress impacts aging, and how organisms respond to stress at the cellular level. Stressors that affect organisms at the cell level can include heat, oxidation, infection, caloric restriction, and more.

“My lab has studied stress responses in three areas: the endoplasmic reticulum, which acts as a ‘factory’ for proteins, lipids, and other molecules within the cell; the mitochondria, where cells’ energy is produced; and the actin cytoskeleton, which helps cells keep or change their shape as needed,” Sanabria said. “Each of these systems has unique ways to respond to stress and maintain their health and function.”

Exposure to stress can be detrimental to cellular health and fitness, Sanabria explained, and thus cells have adapted cellular stress responses that mitigate damage associated with stress exposure. Cellular stress mechanisms decline during aging, making older organisms more sensitive to stress; hyperactivating stress responses can promote resilience and improve general health and longevity, they added.

“When you’re stressed, what’s your capacity to bounce back? The more you can recover from a stressor, the healthier you are, but with aging there is less response and recovery,” Sanabria explained. “But if you take a young person’s stress resilience and give it to an older individual, will they be healthier?”

New gifts support research on cells and stress

Sanabria’s quest to understand how stress and aging impact cellular structures, including the actin cytoskeleton, have been recognized with recent grants supporting their work from the Larry L. Hillblom Foundation, the Glenn Foundation for Medical Research/American Federation for Aging Research, and the Navigage Foundation.

The Hillblom Start-Up Research Grant will provide Sanabria a total of $210,000 over a three-year period to study how the actin cytoskeleton interacts with cells’ energy-producing mitochondria during stress and aging. The organization’s Start-Up grants were designed to help newer scientists begin their independent research careers. Sanabria arrived at the USC Leonard Davis School as an assistant professor in 2021 following a postdoctoral fellowship at UC Berkeley.

Sanabria also received a 2022 Junior Faculty Research Grant from the Glenn Foundation for Medical Research/American Federation for Aging Research in support of their work regarding stress and aging, especially in the endoplasmic reticulum. An organelle known for producing proteins, lipids and other molecules, the endoplasmic reticulum’s unfolded protein response is an important mechanism in preserving healthy protein structure in the face of toxic stress. The $125,000 grant supports Sanabria’s research into how hyperactivating this protective response in specific neurons within the brain can affect health and longevity, which could help identify which neurons are responsible for sensing stress and coordinating the body’s response to it.

In addition, Sanabria has received a $100,000 award from the Navigage Foundation to translate their studies into Alzheimer’s disease. Since they have found that promoting stress resilience is a potential method to increase longevity, the next question is whether it can also be used as a vehicle to combat age-related diseases, Sanabria said. With the support of the Navigage Foundation, Sanabria is investigating whether those that have higher risks for Alzheimer’s Disease had inherently lower capacity to deal with stress and whether increasing stress resilience can actually mitigate the risk – and even slow the progression – of Alzheimer’s disease.

“Large-scale genetic screens identify BET-1 as a cytoskeleton regulator promoting actin function and life span” appeared online in Aging Cell on November 20, 2022. First authors included Gilberto Garcia and Maxim Averbukh of the USC Leonard Davis School and Raz Bar-Ziv of UC Berkeley. Additional authors included Naibedya Dutta, Darius Moaddeli, Toni Castro Torres, Athena Alcala, Sally Hoang, an d Max A. Thorwald of the USC Leonard Davis School; Hanlin Zhang, Wudi Fan, C. Kimberly Tsui, and Erica A. Moehle of UC Berkeley; Nirmalya Dasgupta and Peter D. Adams of the Sanford Burnham Prebys Medical Discovery Institute; and Ophir Shalem of the University of Pennsylvania.

Additional funding for this study came from National Institutes of Health grants T32AG052374 and R01 AG071861, Larry L. Hillblom Foundation Fellowships 019-A-023 and 2020-A-018-FEL, National Institute on Aging grants F32AG069388 and R00AG065200, and National Institute of General Medical Sciences grant 1DP2GM137416-01.

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